May 2022 | VOL. 21, NO. 5| www.McGowan.pitt.edu
We previously reported the results of a study conducted by researchers at the University of Pittsburgh School of Medicine and the McGowan Institute for Regenerative Medicine that showed significant improvement in strength and range of motion, as well as evidence for skeletal muscle regeneration, in 13 patients who were surgically implanted with bioscaffolds derived from pig tissue to treat muscle injuries. The patients had failed to respond to conventional treatment before use of the extracellular matrix (ECM). The findings were published online in npj Regenerative Medicine.
In the prior human subject clinical trial (NCT01292876, PRO10010500) the researchers evaluated a regenerative medicine approach using ECM for volumetric muscle loss (VML) treatment. ECM scaffolds were implanted and combined with aggressive and early physical therapy in 13 subjects, then followed for 24-28 weeks after implantation. Histomorphological assessments collected from core needle biopsies identified formation of new, vascularized, innervated islands of skeletal muscle within the implantation site. Subjects demonstrated increased force production in physical therapy evaluations and improved functional task performance when compared with pre-operative performance. By 6 months after ECM implantation, subjects had a 37.3% improvement in strength and 27.1% improvement in range-of-motion tasks. Additionally, changes in nerve conduction study (NCS) and electromyography (EMG) before and after ECM implantation were measured. 63% of study participants experienced improvements in NCS or EMG within the scaffold remodeling site, indicating clinical improvement in muscle strength. The promising functional and regenerative results from this early study encourages evidence of ECM bioscaffolding as a viable treatment to VML.
The research and clinical teams are now recruiting patients for a second DOD funded clinical trial to further assess the effectiveness of ECM implants to restore muscle function in patients who have lost muscle due to trauma.
This study proposes to use XenMatrix™ AB Surgical Graft which has 510(k) approval intended for implantation to reinforce soft tissue where weakness exists and for surgical repair of damaged or ruptured soft tissue, including abdominal plastic and reconstructive surgery; muscle flap reinforcement; hernia repair including abdominal, inguinal, femoral, diaphragmatic, scrotal, umbilical, and incisional hernias. The graft has an antibiotic coating. This coating has been shown in preclinical in vitro and in vivo testing to reduce or inhibit microbial colonization on the device. The claim of reduction of bacterial colonization of the device has not yet been established with human clinical data, nor has a clinical impact associated with this claim been demonstrated and will need further investigation. This trial proposes to test the applicability and utility of XenMatrix™ AB Surgical Graft in the restoration of function in the setting of volumetric muscle loss after trauma. Ten subjects will be enrolled for participation in the study. Prior to Graft implantation, subjects will receive a pre-operative course of physical therapy for a maximum time period of 16 weeks. A physical therapist will confirm that functional plateau is reached prior to implantation of the Graft. Following Graft implantation, radiographic, functional, and electrophysotherapy outcomes will be measured at various time points up to 24-28 weeks post-operatively. A CT scan or MRI will be collected at screening and pre-operative visits to evaluate tissue volume, then again at post-operative Visit 1 and Visit 6. Physical therapy training will be performed as a research procedure following Graft implantation for a maximum of 30 weeks. Additionally, Physical Therapy evaluations will be conducted at screening, pre-op visit 1, post-op, and at post-op Visits 3, and 4. A small core needle biopsy 1-5 grams will be collected at three time points to conduct histomorphological assessment of the tissue prior to Graft implantation (Operative visit, Visit 2 and at Visit 4).
To explore eligibility and possible enrollment in the new clinical trial please inquire at 412-641 8676, or firstname.lastname@example.org. For more background on this study, listen to the podcast with Dr Badylak.
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Reticular fibers, or reticulin is a type of fiber in connective tissue, composed of type III collagen secreted by reticular cells. Reticular fibers crosslink to form a fine meshwork (reticulin). This network acts as a supporting mesh in soft tissues such as liver, bone marrow, and the tissues and organs of the lymphatic system.
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A mutated gene found in more than 20% to 30% of breast cancer recurrences may help tumors become more aggressive and promote metastasis, according to a pair of new studies that uncover mechanisms behind these processes and point to new therapy targets.
“We’re excited about this research because it addresses an important clinical problem: A huge number of deaths in breast cancer patients are the result of mutations in estrogen receptor genes,” said senior author McGowan Institute for Regenerative Medicine affiliated faculty member Steffi Oesterreich, PhD (pictured), co-leader of the Cancer Biology Program at UPMC Hillman Cancer Center and professor in the University of Pittsburgh School of Medicine Department of Pharmacology & Chemical Biology. “Our study provides a deeper understanding of how these mutations contribute to disease progression and also identifies potential vulnerabilities, which we hope will lead to development of personalized treatment approaches.”
More than 40,000 women die each year from breast cancer in the United States. About two-thirds of tumors express estrogen receptor genes. Hormone therapy can be very effective for these estrogen receptor-positive (ER+) tumors, but in about one-third of cases, the receptor becomes mutated and no longer responds to this treatment.
As a first step toward developing new therapies for these patients, the multi-institutional team led by Dr. Zheqi (Vaciry) Li, who was a postdoctoral associate in Dr. Oesterreich’s lab, took a closer look at tumors harboring estrogen receptor gene ESR1 with a mutation at one of several “hotspots” in the genetic code.
In a new Cancer Research study, the researchers show that these hotspot mutations not only drive resistance to hormone therapy but also promote metastasis, helping breast cancer cells move to other parts of the body. McGowan Institute affiliated faculty member Simon Watkins, PhD, Founder and Director of the Center for Biologic Imaging at the University of Pittsburgh, a member of the Pittsburgh Cancer Institute, and Distinguished Professor and Vice Chairman within the Department of Cell Biology, is a co-author on this study.
According to Dr. Oesterreich, ESR1 is a master regulator of several molecular pathways, including a type of interaction between cells called cell-cell attachment. When the researchers took liquid biopsies from patients with mutated ESR1, they found clusters of tumor cells circulating in the blood.
“We think that this mutation makes tumor cells sticky, so they clump together,” said Dr. Oesterreich, who is also co-director of the Women’s Cancer Research Center, a collaboration between UPMC Hillman and Magee-Womens Research Institute. “This is a novel finding and somewhat unexpected.”
The researchers suspect that these sticky clumps of cells are transported throughout the blood and adhere to healthy tissues, promoting new tumors, or metastases, in other parts of the body.
“This mutation is bad news for cancer prognosis, but the good news is that there are drugs that target cell-cell attachment,” said Dr. Oesterreich. “We hope that this study lays the foundation to test drugs that prevent or treat metastatic breast cancer driven by estrogen receptor mutations.”
In the second study, published in Nature Communications, the researchers found that tumors with ESR1 mutations also had high expression of so-called basal features, which make breast cancers aggressive and difficult to treat.
But this study also offered a silver lining. Mutant tumors had high expression of genes associated with tumor infiltration by macrophages, a type of immune cell that cleans up dead cells and destroys bacteria and other pathogens.
“Previously, it was thought that ER+ tumors are cold, or impenetrable by immune cells, meaning that they don’t respond to immunotherapy,” explained Dr. Oesterreich. “But these findings give us a potential new target for patients with the ESR1 mutant breast cancer: Targeting macrophages could kill the tumor.”
In ongoing work, Dr. Oesterreich and her team seek to confirm immune infiltration in ESR1 mutant tumors collected at other research centers. They are also collaborating with investigators from other institutions to test whether cell-cell attachment involved in metastasis can be blocked with drugs.
Pittwire reports that the University of Pittsburgh has joined a select pool of 56 organizations — and just two universities — to compete for as much as $10 billion in contracts from the Department of Defense to develop health care innovations benefiting both wounded warriors and civilians over the next five years.
Over the next five years, the Defense Health Agency as part of its Omnibus IV solicitation will issue requests for proposals to complete contracts related to military health, spanning research areas such as trauma care, veteran quality of life and acute field care. Pitt, leading a consortium of eight academic and 64 industry partners, will pursue those contracts. The McGowan Institute for Regenerative Medicine and the Center for Military Medicine Research will be at the helm. (Photo Credit: Human Engineering Research Laboratories)
Breathing happens without even thinking about it, but that doesn’t mean it’s simple.
Researchers have debated for years about how a group of brain cells called the preBötzinger complex governs breathing rhythms — and according to a study by two University of Pittsburgh researchers, a new model they’ve created explains many results that other scientists have found about how the process works.
Department of Mathematics Professor and Chair Jonathan Rubin, PhD (pictured), and Postdoctoral Researcher Ryan Phillips, PhD, in the Kenneth P. Dietrich School of Arts and Sciences, published the paper in the journal eLife. Dr. Rubin is an affiliated faculty member of the McGowan Institute for Regenerative Medicine.
To attempt to explain some apparently conflicting experimental results, the researchers started with a model of how specific charged atoms flow in a single brain cell, informed by data from experiments, then scaled up that model to the size of a whole network of cells. The model predicts that the flow of charged calcium atoms could explain patterns that researchers have seen in how brain cells synch up, providing a prediction that researchers can now test in their experiments.
The results, the duo writes, could “unify a wide range of experimental findings” on how brain cells get into rhythm and come to drive the rhythm of our breath.
People with congenital stationary night blindness (CSNB) are unable to distinguish objects in dim-light conditions. This impairment presents challenges, especially where artificial lighting is unavailable or when driving at night.
In 2015, researchers from Penn’s School of Veterinary Medicine learned that dogs could develop a form of inherited night blindness with strong similarities to the condition in people. In 2019, the team identified the gene responsible.
journal, Proceedings of the National Academy of Sciences, they’ve reported a major advance: a gene therapy that returns night vision to dogs born with CSNB. The success of this approach, which targets a group of cells deep in the retina called ON bipolar cells, charts a significant step toward a goal of developing a treatment for both dogs and people with this condition, as well as other vision problems that involve ON bipolar cell function. McGowan Institute for Regenerative Medicine affiliated faculty member Leah Byrne, PhD, Assistant Professor, Department of Ophthalmology, University of Pittsburgh, with secondary appointments in the Departments of Neurobiology and Bioengineering, co-authored the study.
Dogs with CSNB that received a single injection of the gene therapy began to express the healthy LRIT3 protein in their retinas and were able to navigate a maze in dim light. The treatment also appears lasting, with a sustained therapeutic effect lasting a year or longer.
“The results of this pilot study are very promising,” says Keiko Miyadera, DVM, PhD, lead author on the study and an assistant professor at Penn Vet. “In people and dogs with congenital stationary night blindness, the severity of disease is consistent and unchanged throughout their lives. And, we were able to treat these dogs as adults, between 1 and 3 years of age. That makes these findings promising and relevant to the human patient population, as we could theoretically intervene even in adulthood and see an improvement in night vision.”
In the earlier work, the Penn Vet team, working in collaboration with groups from Japan, Germany, and the United States, discovered a population of dogs with CSNB and determined that mutations in the LRIT3 gene were responsible for the dogs’ night vision impairment. The same gene has been implicated in certain cases of human CSNB as well.
This mutation affects the ON bipolar cells’ function, but, unlike in some blinding diseases, the overall structure of the retina as a whole remained intact. That gave the research team hope that supplying a normal copy of the LRIT3 gene could restore night vision to affected dogs.
Yet while Penn Vet researchers from the Division of Experimental Retinal Therapies have developed effective gene therapies for a variety of other blinding disorders, none of these earlier treatments has targeted the ON bipolar cells, located deep within the middle layer of the retina.
“We’ve stepped into the no-man’s land of the retina with this gene therapy,” says William A. Beltran, DVM, PhD, a coauthor and professor at Penn Vet. “This opens the door to treating other diseases that impact the ON bipolar cells.”
The researchers overcame the hurdle of targeting these relatively inaccessible cells with two key findings. First, through a rigorous screening process conducted in collaboration with colleagues at the University of California, Berkeley, led by John Flannery, PhD, and at the University of Pittsburgh led by Dr. Byrne, they identified a vector for the healthy LRIT3 gene that would enable the treatment to reach the intended cells. Second, they paired the healthy gene with a promoter — the genetic sequence that helps initiate the “reading” of the therapeutic gene — that would act in a cell-specific fashion.
“Prior therapies we’ve worked on have targeted photoreceptors or retinal pigment epithelium cells,” says coauthor Gustavo D. Aguirre, VMD, PhD, a Penn Vet professor. “But the promoter we use here is very specific in targeting the ON bipolar cells, which helps avoid potential off-target effects and toxicity.”
The researchers suspect that restoring the functional LRIT3 gene enables signals to cross from the photoreceptor cells to the ON bipolar cells. “LRIT3 is expressed at the ‘finger’ tips of these cells,” says Dr. Beltran. “Introducing this transgene is essentially allowing the two cells to shake hands and communicate again.”
An open question is whether targeting both photoreceptor cells and ON bipolar cells together could lead to even greater improvements in night vision. Other research groups studying these conditions in mice have targeted the therapy to photoreceptor cells and found some vision to be restored, suggesting a possible path to enhance the effects of gene therapy.
And while the therapy enabled functional recovery — dogs were able to navigate a maze when their treated eye was uncovered but not when it was covered — the healthy copy of the gene was only expressed as much as 30% of ON bipolar cells. In follow-up work, the researchers hope to augment this uptake.
“We had great success in this study, but we saw some dogs get better recovery than others,” says Dr. Miyadera. “We’d like to continue working to maximize the therapeutic benefit while still ensuring safety. And we’ve seen that this treatment is durable, but is it lifelong after one injection? That’s something we’d like to find out.”
The team also plans to amend the therapy to use the human version of the LRIT3 gene, a necessary step toward translating the treatment to people with CSNB with an eventual clinical trial.
Collaborators—OmniLife (a health technology communication and collaboration platform), UPMC Children’s Hospital of Pittsburgh, and the Starzl Network—have been awarded a $250,000 SBIR grant from the National Institutes of Health. The grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) will support the “Transplants for Kids” project, which will use AI / machine learning algorithms to align optimal donor grafts with children awaiting liver transplants. This is the first of two anticipated phases of the project with a total of $2M in expected funding.
The clinical principal investigator is the UPMC Children’s Hospital of Pittsburgh’s Chief of Transplant and Starzl Network’s founder, George Mazariegos, MD (pictured). Dr. Mazariegos is also an affiliated faculty member of the McGowan Institute for Regenerative Medicine.
Previous work completed by members of the Starzl Network and the OmniLife research team confirmed significant variance in patient mortality among transplant programs that could be prevented with better liver graft selection. The funded project will confirm the feasibility of a graft selection algorithm that assists the clinical teams with matching candidates with available livers. If successful, hundreds of pediatric patients could benefit from increased access to transplants and decreased wait time.
The study has three objectives:
- Develop a feature space of principal components from combinations of donor, patient, and program characteristics.
- Train supervised machine learning algorithms for predicting matching characteristics for multiple graft types.
- Determine the feasibility of incorporating the algorithms into OmniLife Organ Workflows™ and deliver the predictions at the time of organ offer, through a randomized controlled trial.
The investigation team includes scientific and clinical faculty from the Scientific Registry for Transplant Recipients (SRTR) and the Universities of Pittsburgh, Columbia, San Francisco, Northwestern, and Iowa. The principal investigator is OmniLife’s cofounder and health informatics expert, Eric Pahl, PhD. The team is bolstered by transplant biostatistician Nicholas Wood, PhD, from SRTR and the clinical leaders in pediatric transplantation affiliated with the Starzl Network: Emily Perito, MD, and Kang Sang-Mo, MD, from University of California, San Francisco; Steven Lobritto, MD, from Columbia; Sarah Taylor, MD, from Northwestern; and James Squires, MD, and Kyle Soltys, MD, from UPMC.
In his lab, McGowan Institute for Regenerative Medicine affiliated faculty member Partha Roy, PhD (pictured), Associate Professor of Bioengineering, Cell Biology, and Pathology at the University of Pittsburgh, and his team are focused on studying how alteration in profilin (a G-actin binding protein that is important for actin cytoskeletal regulation and many actin-dependent cellular processes) expression and/or function impacts breast cancer metastasis and angiogenesis. In this overall context, they explore novel post-translational modifications of ABPs and how these modifications impact protein function and actin-dependent biological processes.
Aberrant angiogenesis, the unwanted and destructive formation of new blood vessels, is associated with several eye diseases that can cause blindness, such as diabetic retinopathy, wet age-related macular degeneration, and retinopathy of prematurity. Dr. Roy is a co-principal investigator on the proposal which will examine molecules for preventing and investigating aberrant angiogenesis in the eye. This 2-year project was funded by the National Eye Institute. Other co-principal investigators are Donna Huryn, PhD, David Ryan Koes, PhD, and Andrew VanDemark, PhD.
The project summary/abstract follows:
Proliferative diabetic retinopathy, wet age-related macular degeneration, and retinopathy of prematurity are all diseases of the eye that can lead to blindness and are due to abnormal development of retinal or choroid blood vessels. Although intravitreal anti-angiogenic therapies targeting vascular endothelial growth factor signaling are generally effective for these diseases, spontaneous or acquired resistance is a significant problem and points to the need for high-quality cell-based chemical probes for interrogating angiogenic pathways and developing alternative therapies. To address this unmet need, we propose developing high-quality cell-based chemical probes for the profilin1 (Pfn1)-actin protein-protein interaction. Pfn1 is critical for angiogenesis as it plays a vital role in the dynamic remodeling of the actin cytoskeleton in response to angiogenic signals. We have shown in numerous contexts that inhibition or suppression of Pfn1 leads to reduced angiogenesis and have recently demonstrated that inhibiting Pfn1 reduces the formation of new blood vessels in both ex vivo and in vivo models of retinopathy. We have already identified a validated hit compound that inhibits the Pfn1-actin interaction in biochemical and cell-based assays and confirmed its target engagement in cells. To increase the potency of this inhibitor while maintaining drug-like properties, we will employ an iterative optimization process that will be guided by our structural and cheminformatic models and by the structure-activity relationship that will be developed around the key points of variation during each iteration of compound selection, synthesis, and biological testing. Derivatives will be evaluated in a gated assay cascade to determine their binding affinity for Pfn1 and activity in cells. This iterative process aims to identify an inhibitor of the Pfn1-actin interaction with sub-micromolar potency in both biochemical and cellular assays. Compounds that meet well-defined criteria for novelty and potency in our first round of assays will be validated in the second series of assays to confirm target engagement, selectivity, and other functional utilities (e.g., synergy with an anti-VEGF agent and barrier-function modulatory agent). Successful completion of these studies will result in a potent and specific inhibitor of Pfn1-actin for studying the role of Pfn1 in aberrant angiogenesis and may ultimately lead to a clinical candidate for the treatment of eye disease.
For over 40 years, the Make-A-Wish has been granting life-changing wishes for children and families. Tens of thousands of volunteers, donors, and supporters advance the Make-A-Wish vision to grant the wish of every child diagnosed with a critical illness. In the U.S. and its territories, a wish is granted every 34 minutes. A wish can be that spark that helps these children believe that anything is possible and gives them the strength to fight harder against their illnesses. This one belief guides and inspires Make-A-Wish to grant wishes that change the lives of the kids served.
For children diagnosed with critical illnesses, a wish come true can be a crucial turning point in their lives. One former wish kid, McGowan Institute for Regenerative Medicine affiliated faculty member Kurt Weiss, MD, Associate Professor in the Department of Orthopaedic Surgery’s Division of Musculoskeletal Oncology and Director of the Department’s Cancer Stem Cell Laboratory, agrees.
Dr. Weiss spoke with WTAE Action News about the impact his wish had on him when he was a young boy receiving treatment for osteosarcoma. Osteosarcoma (also called osteogenic sarcoma) is the most common type of cancer that starts in the bones. The cancer cells in these tumors look like early forms of bone cells that normally help make new bone tissue, but the bone tissue in an osteosarcoma is not as strong as that in normal bones.
“I had a weird wish. My wish was to get a new tenor saxophone and play with the University of Notre Dame band at whatever Bowl game they went to that New Year’s,” Dr. Weiss explained.
Wishes are more than just a nice thing. And they are far more than gifts, or singular events in time. Wishes impact everyone involved—wish kids, volunteers, donors, sponsors, medical professionals, and communities. For wish kids, just the act of making their wish come true can give them the courage to comply with their medical treatments. Parents might finally feel like they can be optimistic. And still others might realize all they have to offer the world through volunteer work or philanthropy.
“Where it really helped me and impacted me was in the tough days ahead, that I could look back on the wish and remember fondly how wonderful it was and if I made it through my cancer and continue to do well in school, I could go to Notre Dame,” Dr. Weiss said. He ended up playing in the Notre Dame marching band and was the president of the band when he went to college there.
The headquarters for Make-A-Wish Greater Pennsylvania and West Virginia is located in Pittsburgh. To date, nearly 20,000 wishes have been fulfilled, which is more wishes than any other chapter in the world.
A prognostic model developed by University of Pittsburgh School of Medicine data scientists and UPMC neurotrauma surgeons is the first to use automated brain scans and machine learning to inform outcomes in patients with severe traumatic brain injuries (TBI).
In a study reported in the journal Radiology, the team showed that their advanced machine-learning algorithm can analyze brain scans and relevant clinical data from TBI patients to quickly and accurately predict survival and recovery at six-months after the injury.
“Every day, in hospitals across the United States, care is withdrawn from patients who would have otherwise returned to independent living,” said co-senior author McGowan Institute for Regenerative Medicine affiliated faculty member David Okonkwo, MD, PhD, professor of neurological surgery at Pitt and UPMC. “The majority of people who survive a critical period in an acute care setting make a meaningful recovery—which further underscores the need to identify patients who are more likely to recover.”
It often takes two weeks for TBI patients to emerge from their coma and begin their recoveries—yet severe TBI patients are often taken off life support within the first 72 hours after hospital admission. The new predictive algorithm, validated across two independent patient cohorts, could be used to screen patients shortly after admission and can improve clinicians’ ability to deliver the best care at the right time.
TBI is one of the most pressing public health issues in the U.S.—every year, nearly 3 million people seek TBI care across the nation, and TBI remains a leading cause of death in people under the age of 45.
Recognizing the need for better ways to assist clinicians, the team of data scientists at Pitt set out to leverage their expertise in advanced artificial intelligence to develop a sophisticated tool to understand the nature of each unique patient’s TBI.
“There is a great need for better quantitative tools to help intensive care neurologists and neurosurgeons make more informed decisions for patients in critical condition,” said corresponding author Shandong Wu, PhD, associate professor of radiology, bioengineering and biomedical informatics at Pitt. “This collaboration with Dr. Okonkwo’s team gave us an opportunity to use our expertise in machine learning and medical imaging to develop models that use both brain imaging and other clinically available data to address an unmet need.”
Led by the co-first authors Matthew Pease, MD, and Dooman Arefan, PhD, the group developed a custom artificial intelligence model that processed multiple brain scans from each patient and combined it with an estimate of coma severity and information about the patient’s vital signs, blood tests and heart function. Importantly, because brain imaging techniques evolve over time and image quality can vary dramatically from patient to patient, the researchers accounted for data irregularity by training their model on different image-taking protocols.
The model proved itself by accurately predicting patients’ risk of death and unfavorable outcomes at six months following the traumatic incident. To validate the model, Pitt researchers tested it with two patient cohorts: one of over 500 severe TBI patients previously treated at UPMC and the other an external cohort of 220 patients from 18 institutions across the country, through the TRACK-TBI consortium. The external cohort was critical to test the model’s prediction ability.
“We hope this research shows that AI can provide a tool to improve clinical decision-making early when a TBI patient is admitted to the emergency room, towards yielding a better outcome for the patients,” said Drs. Wu and Okonkwo.
Four paralyzed people in Australia can now operate a computer using only their thoughts thanks to a brain implant developed in part by Carnegie Mellon University’s Douglas Weber, PhD, Professor of Mechanical Engineering and Neuroscience and an affiliated faculty member of the McGowan Institute for Regenerative Medicine. Emily Mullin, Pittsburgh Post-Gazette, recently spoke with Dr. Weber on the status of this brain-computer interface.
The results of the Australian study were presented as part of an exclusive press briefing highlighting breakthrough science at the American Academy of Neurology’s 74th Annual Meeting held in Seattle. The University of Pittsburgh Medical Center and Mount Sinai Hospital in New York will participate in the first U.S. clinical trial to test the device, made by New York City-based company, Synchron.
“An easy way to think about a brain-computer interface is as a substitute for the finger keyboard interactions that we typically use when we are interacting with our computers,” said Dr. Weber, an author on the study. Dr. Weber has advised Synchron on the development of the device. “If you’re paralyzed and you don’t have the ability to use your fingers, you need alternatives to do that.”
Voice recognition is one alternative, but not all devices and apps have voice recognition, and some paralyzed people have lost the use of their voice. Eye-tracking technology is currently the only option for those patients. A brain-computer interface could provide a more seamless way for paralyzed people to communicate and use a computer.
The brain implant in Synchron’s study is about the size of a matchstick. Dubbed the Stentrode, it resembles a heart stent — a mesh device used to treat heart disease by propping open clogged arteries. The Stentrode is delivered to a patient’s brain using a thin catheter that’s snaked through the jugular vein in the neck. It stays inside that blood vessel, traveling all the way to the motor cortex, the part of the brain that directs the body’s movement.
Using 16 sensors that dot its surface, the implant collects brain signals from the motor cortex. These signals are sent to a second device, which is implanted in the chest. It then translates the brain signals into commands for controlling a laptop computer.
“In spite of muscles that are paralyzed, the actions that those muscles are trying to convey can be routed out through signals in the brain,” Dr. Weber said. “Our thoughts drive the actions of our muscles and in the absence of muscles that work, those messages can be conveyed through sensors that are placed in or around the brain to pick up those messages.”
The Australian study participants were all paralyzed from amyotrophic lateral sclerosis, or Lou Gehrig’s disease, a neurodegenerative condition that gradually damages the nerve cells in the brain and spinal cord. Five patients were initially evaluated for the trial, but one was excluded for medical reasons. Four patients ultimately received the device, and researchers monitored them for a year. They found that the device stayed in place and was safe with no major adverse side effects.
For the U.S. trial, UPMC is aiming to enroll an initial three patients with quadriparesis, or paralysis in all four of the limbs, beginning this fall. CMU researchers will work with Synchron on machine learning methods for decoding patients’ brain signals to better interpret their intended actions.
Eva Lai, PhD, made a site visit to the University of Pittsburgh in 2006 when she was building a national research program for regenerative medicine for the U.S. Department of Defense (DoD) to address wounded warriors’ injuries. The program was the Armed Forces Institute of Regenerative Medicine (AFIRM) that resulted in over $200 million in research investments. AFIRM, a multi-institutional, interdisciplinary network working to develop advanced treatment options for our severely wounded servicemen and women, is ongoing. McGowan Institute for Regenerative Medicine Director William Wagner, PhD, is its Chief Science Officer in the collaborative AFIRM effort of the Wake Forest Institute of Regenerative Medicine and the McGowan Institute.
Dr. Lai joined the University of Pittsburgh Swanson School of Engineering in February 2022 as its Director for Partnerships and Innovations with an additional appointment as visiting research professor of mechanical engineering and materials science. She will lead large-scale research at Pitt Engineering and build on her leadership at the DoD and NASA. Her Pitt portfolio will include national security research, industry partnerships, and furthering Pittsburgh’s role as a tech leader. In her new role at the Swanson School, Dr. Lai will begin by collaborating with Heng Ban, PhD, Richard K. Mellon Professor and associate dean for strategic initiatives, on managing and expanding research projects of importance to national security that are funded by the DoD.
“There is so much promise at the University of Pittsburgh,” said Dr. Lai. “There are a lot of innovations, talented researchers, and leaders. I can’t wait to learn more about the University’s capabilities and bring people together to tackle the hard problems that society needs solutions for.”
“The Army needs major university teams with multidisciplinary expertise and tools to help advance fundamental science and engineering in certain applications,” said Dr. Ban, citing a project titled “Enhancing Soldier Protection Against Evolving Threats” that he’s leading with funding from the Army Research Lab. His team, which is developing materials and designs for modern helmets and armors as well as understanding injury mechanisms, includes experts in biology, materials, mechanics, and health sciences from several Pitt schools as well as three other universities.
“Collaboration is key,” Dr. Lai said, noting that Pitt’s Center for Military Medicine Research, directed by McGowan Institute affiliated faculty member Ron Poropatich, MD, is a key partner for the Swanson School’s DoD projects.
Welcome, Dr. Lai!
Illustration: University of Pittsburgh Swanson School of Engineering.
AWARDS AND RECOGNITION
The Lee/Oesterreich Lab of the Magee-Women’s Research Institute is headed by the husband/wife team of Adrian Lee, PhD (pictured left), Professor of Pharmacology & Chemical Biology and Human Genetics, and Director, Institute for Precision Medicine, and Steffi Oesterreich, PhD (pictured right), Professor & Vice Chair, Precision and Translational Pharmacology, and Co-Director of the Women’s Cancer Research Center. Dr. Oesterrich is also an affiliated faculty member of the McGowan Institute for Regenerative Medicine.
During the 2022 Pitt Faculty Honors Convocation Ceremony, both Drs. Lee and Oesterreich received medals recognizing their distinguished accomplishments. Dr. Lee received his medal for his position as the Pittsburgh Foundation Endowed Chair in Precision Medicine. Dr. Oesterrich received her medal for her position as the Shear Family Endowed Chair in Breast Cancer Research.
Members of the Lee/Oesterreich Lab study the molecular basis of breast cancer development and resistance to therapy, with the goal to improve precision medicine and outcomes for breast cancer patients. The laboratory employs a systems biology approach, utilizing a combination of single cell and bulk sequencing, computational methods, and biological models to identify and validate new drivers and therapeutic targets. Hypotheses are tested in vitro and in vivo and then moved to clinical trials.
The majority of studies incorporate analysis of human specimens, in collaboration with a large network of clinicians and nurses. This includes computational analysis and modeling of large biomedical and genomic datasets including electronic health record data.
A major focus of the laboratory is identifying mechanisms of resistance to endocrine therapy, and new approaches to blocking breast cancer metastasis through precision medicine. This includes the study of estrogen receptor (ESR1) mutations and fusions and synergism with growth factor pathways. A special focus is on the understanding of invasive lobular cancer (ILC), the second most common but understudied histological subtype of breast cancer.
Congratulations, Drs. Lee and Oesterreich!
Illustration: Lee/Oesterreich Lab.
McGowan Institute for Regenerative Medicine affiliated faculty member Zachary Freyberg, MD, PhD, Assistant Professor in the Departments of Psychiatry and Cell Biology and an Associate Member of the Pittsburgh Liver Research Center, has been elected a member of The American Society for Clinical Investigation (ASCI).
Founded in 1908, the ASCI is one of the oldest and most esteemed nonprofit honor societies of physician-scientists. The Society is dedicated to the advancement of research that extends our understanding and improves the treatment of diseases of all people, and members are committed to mentoring future generations of physician-scientists of diverse backgrounds and biomedical disciplines. Membership in the ASCI is by election only and serves as a recognition of a researcher’s significant contributions, at a relatively young age, to the understanding of human disease.
“I am both thrilled and honored to have been elected to The American Society for Clinical Investigation,” said Dr. Freyberg. “Foremost, I am grateful to my colleagues in the lab as well as to the Department of Psychiatry for creating such a wonderful environment.”
Dr. Freyberg’s research focuses on improving our understanding of how the mechanisms of dopaminergic neurotransmission are associated with disorders such as addiction, schizophrenia, and Parkinson’s disease. He currently leads a National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01 grant investigating dopaminergic signaling mechanisms in the endocrine pancreas that may be altered by anti-psychotic drugs and lead to profound metabolic disturbances such as weight gain, glucose intolerance, and insulin resistance, as well as increased risk for type 2 diabetes and cardiovascular disease.
Congratulations, Dr. Freyberg!
Each semester, students at the University of Pittsburgh Swanson School of Engineering get the chance to show off their creativity and highlight their designs at the Design EXPO, held this year in the University Club on April 22, 2022. Students prepared their displays showcasing their work from the School’s Capstone Design courses or highlighted concepts and prototypes from the Product Realization and Art of Making courses. The students presented their projects, and judges from industry visited the booths in turn to talk with students and view their work.
The Department of Bioengineering team project, “Pediatric IV Site Stabilization Device,” won 3rd Place in this year’s competition. Two of the students on the project work in the labs of McGowan Institute for Regenerative Medicine faculty members Fabrisia Ambrosio, PhD, and Steven Little, PhD. The winning team members include Reetwan Bandyopadhyay (from the Little Lab), Sydney Borcherding, Pooja Chawla, McKenzie Dowd, Adarsh Mallepally (from the Ambrosio Lab), Darini Rajesh, Jessie Rindfleisch, and Alyssa Zehner.
“Engineering is all about solving problems and finding opportunities for innovation, and the Design EXPO shows that our students are already doing exactly that,” said Mary Besterfield-Sacre, PhD, associate dean for academic affairs and Nickolas A. DeCecco Professor of industrial engineering. “They put their newly learned engineering skills to good use, and they never fail to impress with their ingenuity and creativity.”
Dr. Ambrosio is the Director of Rehabilitation for UPMC International and an Associate Professor in the Department of Physical Medicine and Rehabilitation at the University of Pittsburgh. She holds secondary appointments in the Departments of Bioengineering, Physical Therapy, Orthopaedic Surgery, Microbiology and Molecular Genetics, and Environmental and Occupational Health.
Dr. Little is the Distinguished Professor, the Chairman of the Department of Chemical and Petroleum Engineering, and the William Kepler Whiteford Endowed Professor in the Departments of Chemical and Petroleum Engineering, Bioengineering, Immunology, Ophthalmology, and Pharmaceutical Sciences.
Illustration: University of Pittsburgh Swanson School of Engineering.
The leaders driving advances in medicine, technology, and policy in Pennsylvania populating this year’s Health Care Power 100 list are earning their reputation as the Meds part of the state’s enviable Eds and Meds nickname. They do so by confronting challenges such as COVID, opioid epidemic, families and children at risk, and senior care while also preparing the state, their institutions, and the public for a better, more health-secure future. This list, written by Hilary Danailova for City and State Pennsylvania magazine, recognizes the public officials, health care executives, innovators, academics, advocates, and activists – and their roles in taking care of us.
McGowan Institute for Regenerative Medicine faculty member Bernard Costello, MD, DMD, was named a member of the 2022 Health Care Power 100. As the University of Pittsburgh School of Dental Medicine celebrates 125 years, Dr. Costello, an oral and maxillofacial surgeon, is keeping the school in the vanguard. His name is on two novel guideposts for responsible pain management, a critical part of America’s opioid crisis: the Costello Pain Care Pledge, a practitioner’s commitment, and the Costello Guidelines for Prescribing Pain Medications, a cornerstone of the school’s stance against opioids. Under Dr. Costello’s direction, Pitt Dental Medicine is known for its research into craniofacial disorders and regeneration.
Dr. Costello serves as the Dean of the University of Pittsburgh School of Dental Medicine. He also is a Professor of Oral and Maxillofacial Surgery at the University of Pittsburgh School of Dental Medicine. Dr. Costello is Chief of Pediatric Oral and Maxillofacial Surgery at the UPMC Children’s Hospital of Pittsburgh, and a surgeon with the Cleft and Craniofacial Center. He is Co-Director of the Dentofacial Interdisciplinary Team, and the Director of the Pediatric Craniomaxillofacial Surgery Fellowship Program at the School of Dental Medicine.
Congratulations, Dr. Costello!
The McGowan Institute for Regenerative Medicine applauds its affiliated faculty members who were recently recognized by Pittsburgh Magazine as a Top Doctor. Castle Connolly Top Doctors is a healthcare research company and the official source for Top Doctors for the past 25 years. This year, 18 McGowan Institute affiliated faculty were recognized in the May issue of the magazine. Congratulations are extended to:
Cardiovascular Disease: Joon Sup Lee, MD, Dennis McNamara, MD
Gastroenterology: Michael Pezzone, MD, PhD
Neurological Surgery: David Okonkwo, MD, PhD
Ophthalmology: Ian Conner, MD, PhD
Orthopedic Surgery: MaCalus Hogan, MD, MBA, Kurt Weiss, MD
Otolaryngology: Joseph Dohar, MD, Carl Snyderman, MD, MBA
Pathology: Anthony Demetris, MD
Pediatric Cardiology: Jacqueline Kreutzer, MD
Pediatric Surgery: George Gittes, MD
Plastic Surgery: Howard Edington, MD, Michael Gimbel, MD, Peter Rubin, MD, Mario Solari, MD
Surgery: George Mazariegos, MD
Urogynecology/Female Pelvic Medicine & Reconstructive Surgery: Pamela Moalli, MD, PhD
The Regenerative Medicine Podcasts remain a popular web destination. Informative and entertaining, these are the most recent interviews:
#233 –– Dr. Stephen Badylak summarizes the current clinical trial on restoring muscle loss due to trauma and outlines how to apply for possible inclusion in this study.
Visit www.regenerativemedicinetoday.com to keep abreast of the new interviews.
Author: Zheqi Li, Yang Wu, Megan E Yates, Nilgun Tasdemir, Amir Bahreini, Jian Chen, Kevin M Levine, Nolan M Priedigkeit, Azadeh Nasrazadani, Simak Ali, Laki Buluwela, Spencer Arnesen, Jason Gertz, Jennifer K Richer, Benjamin Troness, Dorraya El-Ashry, Qiang Zhang, Lorenzo Gerratana, Youbin Zhang, Massimo Cristofanilli, Maritza A Montanez, Prithu Sundd, Callen T Wallace, Simon C Watkins, Caterina Fumagalli, Elena Guerini-Rocco, Li Zhu, George C Tseng, Nikhil Wagle, Jason S Carroll, Paul Jank, Carsten Denkert, Maria M Karsten, Jens-Uwe Blohmer, Ben H Park, Peter C Lucas, Jennifer M Atkinson, Adrian V Lee, Steffi Oesterreich
Title: Hotspot ESR1 Mutations Are Multimodal and Contextual Modulators of Breast Cancer Metastasis
Summary: Constitutively active estrogen receptor α (ER/ESR1) mutations have been identified in approximately one-third of ER+ metastatic breast cancers. Although these mutations are known as mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence of ESR1 mutations exclusively in distant but not local recurrences in five independent breast cancer cohorts. In concordance with transcriptomic profiling of ESR1-mutant tumors, genome-edited ESR1 Y537S and D538G-mutant cell models exhibited a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and the TIMP3/MMP axis, which functionally conferred enhanced cell-cell contacts while decreasing cell-extracellular matrix adhesion. In vivo studies showed ESR1-mutant cells were associated with larger multicellular circulating tumor cell (CTC) clusters with increased compactness compared with ESR1 wild-type CTCs. These preclinical findings translated to clinical observations, where CTC clusters were enriched in patients with ESR1-mutated metastatic breast cancer. Conversely, context-dependent migratory phenotypes revealed cotargeting of Wnt and ER as a vulnerability in a D538G cell model. Mechanistically, mutant ESR1 exhibited noncanonical regulation of several metastatic pathways, including secondary transcriptional regulation and de novo FOXA1-driven chromatin remodeling. Collectively, these data provide evidence for ESR1 mutation-modulated metastasis and suggest future therapeutic strategies for targeting ESR1-mutant breast cancer.
Significance: Context- and allele-dependent transcriptome and cistrome reprogramming in mutant ESR1 cell models elicit diverse metastatic phenotypes related to cell adhesion and migration, which can be pharmacologically targeted in metastatic breast cancer.
Source: Cancer Research. 2022 Apr 1;82(7):1321-1339. doi: 10.1158/0008-5472.CAN-21-2576.
PI: Eric Lagasse
Title: Hepatocyte Isolation Extension
Description: Obesity is a complex medical condition caused by dysregulation of systemic metabolism, excessive accumulation of body fat, insulin resistance and a variety of additional health issues. Hepatocytes produce bile acids, which are recognized as key regulators of systemic metabolism, particularly systemic energy expenditure. In this pilot study, we propose experiments to transplant hepatocytes into lymph nodes of mice under fat-induced diet and compare to transplant of brown fat tissue into lymph nodes for an effective treatment of metabolic syndrome.
Statement of Work: Cell-based therapy is a promising approach to generate hepatic functions in patients suffering from a variety of liver diseases. LyGenesis Inc. is a startup company focused on developing technology that enables a patient’s own lymph nodes to be used as bioreactors for hepatocyte transplantation and regeneration of an ectopic liver.
The goal of this study is to demonstrate that transplanted hepatocytes into lymph nodes of mice under fat-induced diet could be an effective treatment of metabolic syndrome. This study will be compared to transplant of brown adipose tissue into lymph nodes.
Background and Rational: Obesity is a complex medical condition caused by dysregulation of systemic metabolism, excessive accumulation of body fat, insulin resistance and a variety of additional health issues. Hepatocytes produce bile acids, which are recognized as key regulators of systemic metabolism, particularly systemic energy expenditure. In this pilot study, we propose experiments to transplant hepatocytes into lymph nodes of mice under fat-induced diet and compare to transplant of brown fat tissue into lymph nodes for an effective treatment of metabolic syndrome.
Research Plan Overview and Approach: C57BL/6J mice will be separated in 4 groups (No high fat diet, high fat diet, high fat diet with transplantation of cells in lymph nodes, high fat diet with transplantation of cells in peritoneal fat). For the animal under high fat diet (HFD), the diet will be induced for 6 weeks. Body weight (1x/week), basal non fasting blood glucose, glucose tolerance test, serum triglyceride, low density cholesterol, and serum IGF1, IL-6 and FGF21 data will be collected before the 6 weeks HFD and at week 6 of HFD. Animal will be transplanted with cells (hepatocytes or brown adipose tissue) with continue HFD the next 8 weeks, transferred to C3M core (The Center for Metabolism and Mitochondrial Medicine) for metabolic monitoring (Sable Systems Promethion metabolic cages and GTT) and possible Insulin Sensitivity by Hyperinsulinemic Euglycemic Clamp before necropsy.
Term: May 1, 2022 – June 30, 2023